Glomerulonephritis (GN) is accompanied by changes in the glomerulus including increased permeability of the glomerular basement membrane (GBM) and detachment of podocytes from the GBM. The mechanisms responsible for these changes are not known. The hypothesis of the proposed research is that cysteine proteinases released at the glomerulus are involved in the degradation of GBM in glomerulonephritis. This hypothesis is based on two findings: 1) cysteine proteinase Cathepsins B and L are present in the glomerulus (our work), and 2) reports by several investigators (including the PI) that these proteinases degrade GBM in vitro. This hypothesis will be tested in rats with the use of two animal models of GN: 1) Heymann nephritis which mimics membranous GN in humans, and 2) puromycin aminonucleoside-induced GN which resembles minimal lesion disease in children. The proposed research intends to 1) measure and compare the activities of cathepsins B and L in glomeruli, urines and sera isolated from rats with induced GN, prior to glomerular injury and during injury; 2) test exogenously administered inhibitors and activators of cathepsins B and L for their effect on proteinuria, the hallmark of glomerular disease; and 3) isolate and characterize cathepsins B and L from rat kidneys. Glomerular disease is the major cause of end stage renal failure. A better understanding of the mechanisms of glomerular damage is essential to the development completion of the work proposed here will provide information on the potential role of cysteine proteinases in the development of GN, and will enhance our understanding of the possible mechanisms by which damage to the GBM occurs in GN.